Retaining polar lipid head group identity by linking drugs to acyl chains to increase drug targeting would represent a significant accomplishment. The ability to direct material to specific locations reduces the need to saturate all pharmacological compartments to achieve therapeutic levels in one. The Phase I research proposed will determine the feasibility of delivering pharmaceutical agents linked to polar lipids with their specific head groups intact. These studies should provide statistically compelling experimental data supporting the hypothesis that AE6C(3'-Azido- 2',3',dideoxythymidine [AZT] linked to ceramide), readily crosses the blood brain barrier and exhibits superior brain and CNS accumulation, antiviral activity, and lower cellular and marrow toxicity compared to AZT. Enhanced brain and CNS accumulation of AZT is likely to be very important in combating AIDS-related dementia. Utilizing an in vitro approach, we will determine whether AE6C can establish an effective cellular reservoir capable of providing a constant drug supply. In patients, this reservoir would decrease dosage frequency and the amount of drug required for therapy, thereby reducing stress and increasing patient compliance. A second drug utilizing AZT linked to phosphotidylglycerol, AE6PG, exhibits promising structural characteristics, will be synthesized and it's pharmacological and antiviral properties evaluated. PROPOSED COMMERCIAL APPLICATION: Linking drugs to polar lipid acyl chains represents an opportunity to improve drug action by directing and retaining drug where it is needed. Development of the polar lipid AZT- linked drugs proposed is likely to be important in the battle against HIV and other virus infections. The ability to deliver AZT and other drugs across the blood brain barrier, while decreasing both the dose required and attendant toxicities and patient discomfort is important and desirable. Likewise other lipids and drugs can be used to direct material preferentially to organs and locations and maybe of help in addressing the resistance problem. Significantly, it provides a platform technology applicable to other drugs presently in use. Development of this drug delivery approach will be significant and timely, as it addresses and overcomes many major shortcomings of currently available antiviral drugs.